9-129814061-TCTC-T

Variant names:

• chr9-129814061-TCTC-T
• rs80358233
• NM_000113.3:c.907_909delGAG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM4_Supporting PP5_Very_Strong

The NM_000113.3(TOR1A):​c.907_909delGAG​(p.Glu303del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000052 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001434932: Functional assays and in vivo animal models demonstrated that this deletion affect the function of the protein [ PMID 18940237, 24930953, 19651773, 24951854, 19339278]." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: TOR1A NM_000113.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 O:1
• Conservation: PhyloP100: 4.74
• Publications: 6 publications found

Genes affected

TOR1A (HGNC:3098): (torsin family 1 member A) The protein encoded by this gene is a member of the AAA family of adenosine triphosphatases (ATPases), is related to the Clp protease/heat shock family and is expressed prominently in the substantia nigra pars compacta. Mutations in this gene result in the autosomal dominant disorder, torsion dystonia 1. [provided by RefSeq, Jul 2008]

TOR1A Gene-Disease associations (from GenCC):

• early-onset generalized limb-onset dystonia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• arthrogryposis multiplex congenita 5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001434932: Functional assays and in vivo animal models demonstrated that this deletion affect the function of the protein [ PMID 18940237, 24930953, 19651773, 24951854, 19339278].; SCV002011944: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24930953).; SCV004101509: Experimental studies have shown that this variant affects TOR1A function (Hettich et. al., 2014; Vulinovic et. al., 201).; SCV004801528: "In vitro analysis of the p.Glu303del variant in BHK21 cells, neurons, and patient fibroblasts demonstrated altered cellular localization and formation of spheroid bodies in the nuclear envelope (Goodchild et al. 2008)."; SCV005921326: "This variant has previously been reported in patients affected with primary torsion dystonia, functional assays and in-vivo animal models demonstrated that this deletion affects the function of the protein." PMID: 24930953; SCV000491317: Published functional studies demonstrate that c.907_909delGAG results in abnormal cellular localization and aggregation of the misfolded protein (Gordon et al., 2008; Hettich et al., 2014); SCV000283510: Experimental studies have shown that this variant affects TOR1A function (PMID: 18940237, 19339278, 19651773, 24930953, 24931141).; SCV001444755: Functional and structural studies demonstrate that this variant results in weakened and defective protein function (Zhao, 2013; Demircioglu, 2016).; SCV004046095: Functional studies indicate that this variant causes misfolding of the protein and results in its abnormal cellular localization and aggregation (PMID: 8940237, 24930953, 19651773, 24951854, 19339278).; SCV004116561: Functional studies support its pathogenicity (Gordon and Gonzalez-Alegre. 2008. PubMed ID: 18940237; Hettich et al. 2014. PubMed ID: 24930953; Ozelius et al. 1997. PubMed ID: 9288096).
• PM4: Nonframeshift variant in NON repetitive region in NM_000113.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-129814061-TCTC-T is Pathogenic according to our data. Variant chr9-129814061-TCTC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000113.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1A	NM_000113.3	MANE Select	c.907_909delGAG	p.Glu303del	conservative_inframe_deletion	Exon 5 of 5	NP_000104.1	O14656-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1A	ENST00000351698.5	TSL:1 MANE Select	c.907_909delGAG	p.Glu303del	conservative_inframe_deletion	Exon 5 of 5	ENSP00000345719.4	O14656-1
	TOR1A	ENST00000651202.1		c.*175_*177delGAG		3_prime_UTR	Exon 6 of 6	ENSP00000498222.1	A0A494BZT7
	TOR1A	ENST00000474192.1	TSL:3	n.491_493delGAG		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251492 AF XY: 0.000132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461892 Hom.: 0 AF XY: 0.0000509 AC XY: 37 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1112010

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.0000718

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Early-onset generalized limb-onset dystonia (12)
7	-	-	not provided (7)
3	-	-	TOR1A-related disorder (3)
2	-	-	Dystonic disorder (2)
1	-	-	Arthrogryposis multiplex congenita 5 (1)
1	-	-	Early-onset generalized limb-onset dystonia;C5436453:Arthrogryposis multiplex congenita 5 (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=48/52	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80358233; hg19: chr9-132576340;